Description:
This randomized phase III trial studies rituximab with bendamustine hydrochloride or
ibrutinib to see how well they work compared to ibrutinib alone in treating older patients
with previously untreated chronic lymphocytic leukemia. Monoclonal antibodies, such as
rituximab, may block cancer growth in different ways by targeting certain cells. Drugs used
in chemotherapy, such as bendamustine hydrochloride, work in different ways to stop the
growth of cancer cells, either by killing the cells, by stopping them from dividing, or by
stopping them from spreading. Ibrutinib may stop the growth of cancer cells by blocking some
of the enzymes needed for cell growth. It is not yet known whether rituximab with
bendamustine hydrochloride may work better than rituximab and ibrutinib or ibrutinib alone in
treating chronic lymphocytic leukemia.
Title
- Brief Title: Rituximab and Bendamustine Hydrochloride, Rituximab and Ibrutinib, or Ibrutinib Alone in Treating Older Patients With Previously Untreated Chronic Lymphocytic Leukemia
- Official Title: A Randomized Phase III Study of Bendamustine Plus Rituximab Versus Ibrutinib Plus Rituximab Versus Ibrutinib Alone in Untreated Older Patients (>/= 65 Years of Age) With Chronic Lymphocytic Leukemia (CLL)
Clinical Trial IDs
- ORG STUDY ID:
NCI-2013-01220
- SECONDARY ID:
NCI-2013-01220
- SECONDARY ID:
ALLIANCE A041202
- SECONDARY ID:
A041202
- SECONDARY ID:
A041202
- SECONDARY ID:
K23CA178183
- SECONDARY ID:
R01CA183444
- SECONDARY ID:
U10CA180821
- SECONDARY ID:
U10CA031946
- NCT ID:
NCT01886872
Conditions
- Stage I Chronic Lymphocytic Leukemia
- Stage II Chronic Lymphocytic Leukemia
- Stage III Chronic Lymphocytic Leukemia
- Stage IV Chronic Lymphocytic Leukemia
Interventions
| Drug | Synonyms | Arms |
|---|
| Bendamustine Hydrochloride | Belrapzo, Bendamustin Hydrochloride, Bendeka, Cytostasan Hydrochloride, Levact, Ribomustin, SyB L-0501, Treanda | Arm I (rituximab, bendamustine hydrochloride) |
| Ibrutinib | BTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765 | Arm II (ibrutinib) |
| Rituximab | ABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab ABBS, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar JHL1101, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, Rituximab Biosimilar SIBP-02, rituximab biosimilar TQB2303, rituximab-abbs, RTXM83, Truxima | Arm I (rituximab, bendamustine hydrochloride) |
Purpose
This randomized phase III trial studies rituximab with bendamustine hydrochloride or
ibrutinib to see how well they work compared to ibrutinib alone in treating older patients
with previously untreated chronic lymphocytic leukemia. Monoclonal antibodies, such as
rituximab, may block cancer growth in different ways by targeting certain cells. Drugs used
in chemotherapy, such as bendamustine hydrochloride, work in different ways to stop the
growth of cancer cells, either by killing the cells, by stopping them from dividing, or by
stopping them from spreading. Ibrutinib may stop the growth of cancer cells by blocking some
of the enzymes needed for cell growth. It is not yet known whether rituximab with
bendamustine hydrochloride may work better than rituximab and ibrutinib or ibrutinib alone in
treating chronic lymphocytic leukemia.
Detailed Description
PRIMARY OBJECTIVES:
I. To determine whether progression free survival (PFS) is superior after therapy with
bendamustine (bendamustine hydrochloride) in combination with rituximab, ibrutinib alone, or
ibrutinib in combination with rituximab in patients age 65 or older with previously untreated
chronic lymphocytic leukemia (CLL).
SECONDARY OBJECTIVES:
I. To determine 2-year PFS in each of the three treatment arms. II. To determine which
treatment arm produces superior overall survival (OS). III. To determine the complete
response (CR) rate, complete and nodular partial response (CR/nPR) rate, and overall response
(PR+nPR+CR) rate (ORR) among the three treatment arms and compare these arms.
IV. To determine the impact of minimal residual disease (MRD)-negative disease at time of CR
documentation and at 2 years on PFS and OS in each of the treatment arms.
V. To determine duration of response after each of the three treatments and compare these
treatment arms.
VI. To determine toxicity and tolerability of the three treatment regimens.
OTHER PRE-SPECIFIED OBJECTIVES:
I. To determine whether baseline cytogenetic markers, zeta-chain (TCR) associated protein
kinase 70kDa (Zap-70) methylation, immunoglobulin variable region (IgVH) mutational status,
or select deoxyribonucleic acid (DNA) mutations predict outcomes or time to response in these
three arms.
II. To determine whether local fluorescent in situ hybridization (FISH) results for
del(11q22.3) and del(17p13.1) are consistent with central analysis.
III. To determine whether baseline micro ribonucleic acid (RNA) and gene expression markers
are correlated with clinical outcomes of interest (e.g. progression-free and alive at 2 years
versus not), as well as to explore changes in microRNA expression from baseline to
post-treatment time points, with a focus on those with persistent lymphocytosis and relapse.
IV. To determine whether eradication of MRD predicts longer duration of response with
standard therapy and ibrutinib-based regimens.
V. To describe the baseline functional status, comorbid medical conditions, and number of
medications of older CLL patients who meet criteria for therapy.
VI. To determine how functional status changes with therapy using baseline to 3-month
evaluation and end-of-study/2-year evaluation; to determine whether this change is different
among the treatment groups.
VII. To determine whether geriatric assessment variables known to be associated with
chemotherapy toxicity in other disease groups can also predict therapy-associated toxicity in
the CLL population.
VIII. To assess whether the Fc fragment of IgG, low affinity IIIa, receptor (CD16a) (FCGR3A)
polymorphism (rs396991) is correlated with depth of response (MRD status) to ibrutinib plus
rituximab after 6 cycles, with secondary endpoints CR rate, rapidity of response, and
progression-free survival (PFS).
IX. To assess whether complement component 1, q subcomponent, A chain (C1QA) polymorphism
(rs172378) is correlated with MRD status, CR rate, rapidity of response, and PFS.
OUTLINE: Patients are randomized to 1 of 3 treatment arms.
ARM I: Patients receive rituximab intravenously (IV) on day 1 (day 0 course 1) and
bendamustine hydrochloride IV over 30 minutes on days 1-2. Treatment repeats every 28 days
for 6 courses in the absence of disease progression or unacceptable toxicity. Patients
experiencing disease progression may crossover to Arm II.
ARM II: Patients receive ibrutinib orally (PO) daily on days 1-28. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.
ARM III: Patients receive ibrutinib as in Arm II. Patients receive rituximab IV on days 1, 8,
15, and 22 of course 2 and on day 1 of courses 3-6. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months for up to 10
years.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Arm I (rituximab, bendamustine hydrochloride) | Active Comparator | Patients receive rituximab IV on day 1 (day 0 course 1) and bendamustine hydrochloride IV over 30 minutes on days 1-2. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm II. | - Bendamustine Hydrochloride
- Rituximab
|
| Arm II (ibrutinib) | Experimental | Patients receive ibrutinib PO daily. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | |
| Arm III (ibrutinib, rituximab) | Experimental | Patients receive ibrutinib as in Arm II. Patients receive rituximab IV on days 1, 8, 15, and 22 of course 2 and on day 1 of courses 3-6. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | |
Eligibility Criteria
Inclusion Criteria:
- Patients must be diagnosed with CLL in accordance with International Workshop on
Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria that includes all of the following:
- >= 5 x 10^9 B lymphocytes (5000/uL) in the peripheral blood
- On morphologic review, the leukemic cells must be small mature lymphocytes, and
prolymphocytes must not exceed 55% of the blood lymphocytes
- CLL cells on immunophenotype (performed locally) must reveal a clonal B-cell
population, which express the B cell surface markers of cluster of
differentiation (CD)19 and CD20, as well as the T-cell antigen CD5; patients with
bright surface immunoglobulin expression or lack of CD23 expression in > 10% of
cells must lack t(11;14) translocation by interphase cytogenetics
- Patients must be intermediate or high-risk Rai stage CLL
- Intermediate risk (formerly Rai stage I/II) is defined by lymphocytosis plus
enlarged lymph nodes at any site, with or without hepatomegaly or splenomegaly
- High risk (formerly Rai stage III/IV) is defined by lymphocytosis with or without
enlarged nodes and spleen plus disease-related anemia (hemoglobin < 11 g/dL) or
thrombocytopenia (platelet count < 100 x 10^9/L) that is not attributable to
autoimmune hemolytic anemia or thrombocytopenia
- Patients must meet criteria for treatment as defined by IWCLL 2008 guidelines which
includes at least one of the following criteria:
- Evidence of marrow failure as manifested by the development or worsening of
anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or
thrombocytopenia)
- Massive (>= 6 cm below the costal margin), progressive or symptomatic
splenomegaly
- Massive nodes (>= 10 cm) or progressive or symptomatic lymphadenopathy
- Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard
therapy
- Constitutional symptoms, which include any of the following:
- Unintentional weight loss of 10% or more within 6 months
- Significant fatigue
- Fevers > 100.5 degrees F for 2 weeks or more without evidence of infection
- Night sweats > 1 month without evidence of infection
- Prior treatment
- Patients must not have had prior therapy for CLL (except palliative steroids or
treatment of autoimmune complications of CLL with rituximab or steroids)
- Treatment with rituximab and/or high dose corticosteroids for autoimmune
complications of CLL must be complete at least 4 weeks prior to enrollment;
palliative steroids must be at a dose not higher than 20 mg/day of prednisone or
equivalent corticosteroid at the time of registration
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- Patients with active hepatitis B defined by hepatitis B surface antigen positivity or
core antibody positivity in the presence of hepatitis B DNA are not eligible for this
study; patients with a positive hepatitis B core antibody but with negative hepatitis
B DNA may participate, but must have hepatitis serologies and hepatitis B DNA
monitored periodically by the treating physician
- Intravenous immunoglobulin (IVIG) can cause a false positive hepatitis B
serology; if patients receiving routine IVIG have core antibody or surface
antigen positivity without evidence of active viremia (negative hepatitis B DNA)
they may still participate in the study, but should have hepatitis serologies and
hepatitis B DNA monitored periodically by the treating physician
- Patients must not be receiving active systemic anticoagulation with heparin or
warfarin; patients must be off warfarin therapy for at least 30 days prior to
enrollment
- Patients with class III or class IV heart failure by New York Heart Association, those
with unstable angina, and those with uncontrolled arrhythmia are not eligible
- Patients who have had a myocardial infarction, intracranial bleed, or stroke within
the past 6 months are not eligible
- Patients with human immunodeficiency virus (HIV) are eligible if their CD4 count is >=
350 cells/mm^3 and if they are not taking prohibited cytochrome (CYP)-interacting
medications
- Patients must not have any history of Richter's transformation or prolymphocytic
leukemia (prolymphocytes in blood > 55%)
- Patients must not require more than 20 mg prednisone or equivalent corticosteroid
daily
- Patients must not have uncontrolled active systemic infection requiring intravenous
antibiotics
- Patients must not have continued requirement for therapy with a strong cytochrome P450
3A4/5 (CYP3A4/5) inhibitor or inducer
- Patients must not have a known allergy to mannitol
- Patients must not have prior significant hypersensitivity to rituximab (not including
infusion reactions)
- Patients may not have had major surgery within 10 days of enrollment, or minor surgery
within 7 days of enrollment; examples of minor surgery include dental surgery,
insertion of a venous access device, skin biopsy, or aspiration of a joint; the
decision about whether a surgery is major or minor can be made at the discretion of
the treating physician
- Absolute neutrophil count (ANC) >= 1,000/uL unless due to bone marrow involvement
- Aspartate aminotransferase (AST) or alanine aminotransferase (AST) =< 2.5 x upper
limits of normal except if due to disease infiltration of the liver
- Bilirubin =< 1.5 x upper limits of normal (unless due to liver involvement, hemolysis,
or Gilbert's disease)
- Creatinine clearance >= 40 mL/min
- To be calculated by modified Cockcroft-Gault formula
- Platelet count (untransfused) >= 30,000/uL
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 65 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Progression Free Survival (PFS) |
| Time Frame: | Time from study entry to the time of documented disease progression or death. The analysis was event driven, performed at 2.5 years after the last patient enrolled;up to 4 years. |
| Safety Issue: | |
| Description: | The Kaplan-Meier method will be used to estimate the progression free survival distributions for each arm, with median estimates provided. Progression is defined as any one of the following: an increase in number of blood lymphocytes by >= 50% with >= 5000 B lymphocytes/mL in patients on Arm A or those on Arms 2 or 3 no longer receiving ibrutinib, >= 50% increase in the products of at least 2 lymph nodes on 2 consecutive determination 2 weeks apart, >= 50% increase in the size of the liver/spleen, transformation to a more aggressive histology, progression of any cytopenia (i.e. decrease of Hb levels > 2g/dL). Progression free survival time will be the time to either progression or death whichever occurs first. |
Secondary Outcome Measures
| Measure: | Progression Free Survival (PFS) Rate at 2 Years |
| Time Frame: | Time from study entry to the time of documented disease progression or death, assessed up to 2 years |
| Safety Issue: | |
| Description: | The Kaplan-Meier method will be used to estimate the rate of progression free survival at 2 years in each treatment arm. Progression is defined as any one of the following: an increase in number of blood lymphocytes by >= 50%, >= 50% increase in the products of at least 2 lymph nodes on 2 consecutive determination 2 weeks apart, >= 50% increase in the size of the liver/spleen, transformation to a more aggressive histology, progression of any cytopenia (i.e. decrease of Hb levels > 2g/dL). Progression free survival time will be the time to either progression or death whichever occurs first. |
| Measure: | Overall Survival (OS) at 2 Years |
| Time Frame: | From the date of registration to the date of death, assessed up to 2 years |
| Safety Issue: | |
| Description: | The Kaplan-Meier method will be used to estimate the rate of overall survival at 2 years in each treatment arm. OS will be measured from the date of registration to the date of the event (i.e., death) or the date of last follow-up to evaluate that event. Patients who are event-free at their last follow-up evaluation will be censored at that time point. |
| Measure: | Duration of Response (DOR) (Complete Response [CR], CCR, Nodular Partial Response [nPR], Partial Response [PR], and PRL) |
| Time Frame: | From the date of first response until progression or death, performed at 2.5 years after the last patient enrolled; up to 4 years. |
| Safety Issue: | |
| Description: | The Kaplan-Meier method will be used to estimate median DOR. DOR is the time from first objective status to progression or death. CR requires all of the following: absence of lymphadenopathy > 1.5 cm on physical exam/CT scan, no hepatomegaly/splenomegaly on physical exam, no clonal B-cells in the blood, Normal CBC, bone marrow aspirate & biopsy must be normocellular for age. PR requires >= 50% decrease in peripheral lymphocyte count from pre-treatment value, >= 50% reduction in lymphadenopathy, and/or ≥ 50% reduction in splenomegaly/hepatomegaly. CR with exception of having bone marrow lymphoid CLL nodules will be considered a nodular PR (nPR). CR with exception of not having a bone marrow biopsy performed will be considered a clinical CR (CCR). PR with the exception of having less than a 50% reduction in peripheral lymphocyte count will be considered a PR except persistent lymphocytosis (PRL). |
| Measure: | Percentage of Patients Achieving Any Response to Treatment (Overall Response Rate [ORR] [Complete Response [CR], CCR, Nodular Partial Response [nPR], Partial Response [PR], and PRL]) |
| Time Frame: | Performed at 2.5 years after the last patient enrolled;up to 4 years. |
| Safety Issue: | |
| Description: | Complete response (CR) requires all of the following: absence of lymphadenopathy >1.5 cm on physical exam/CT scan, no hepatomegaly/splenomegaly on physical exam, no clonal B-cells in the blood, Normal CBC, bone marrow aspirate & biopsy must be normocellular for age. Partial response (PR) requires >= 50% decrease in peripheral lymphocyte count from pre-treatment value, >= 50% reduction in lymphadenopathy, and/or ≥ 50% reduction in splenomegaly/hepatomegaly. CR with exception of having bone marrow lymphoid CLL nodules will be considered a nodular PR (nPR). CR with exception of not having a bone marrow biopsy performed will be considered a clinical CR (CCR). PR with the exception of having less than a 50% reduction in peripheral lymphocyte count will be considered a PR except persistent lymphocytosis (PRL).Overall response rate and corresponding exact binomial 95% CI provided. |
| Measure: | Percentage of Patients Achieving a Biopsy-proven Complete Response (CR) |
| Time Frame: | Performed at 2.5 years after the last patient enrolled; up to 4 years. |
| Safety Issue: | |
| Description: | Complete response (CR) requires all of the following: absence of lymphadenopathy > 1.5 cm on physical exam/CT scan, no hepatomegaly or splenomegaly on physical exam, no clonal B-cells in the blood, Normal CBC, bone marrow aspirate and biopsy must be normocellular for age. Complete response rate and corresponding exact binomial 95% confidence intervals provided. |
| Measure: | Percentage of Patients Achieving Complete (CR and CCR) or Nodular Partial Response (nPR) |
| Time Frame: | Performed at 2.5 years after the last patient enrolled; up to 4 years. |
| Safety Issue: | |
| Description: | Complete response (CR) requires all of the following: absence of lymphadenopathy > 1.5 cm on physical exam/CT scan, no hepatomegaly or splenomegaly on physical exam, no clonal B-cells in the blood, Normal CBC, bone marrow aspirate and biopsy must be normocellular for age. CR with exception of having bone marrow lymphoid CLL nodules will be considered a nodular PR (nPR). CR with exception of not having a bone marrow biopsy performed will be considered a clinical CR (CCR). Response rate and corresponding exact binomial 95% confidence intervals provided. |
| Measure: | Percentage of Patients Who Attain Minimal Residual Disease (MRD) Negative Status |
| Time Frame: | Cycle 9 Day 1 Evaluation |
| Safety Issue: | |
| Description: | Estimated using the number of patients who achieve minimal residual disease divided by the total number randomized to that treatment arm. Corresponding exact binomial 95% confidence intervals for MRD rates will be calculated. |
| Measure: | The Rate of Grade 3, 4, or 5 Treatment-related Non-hematologic Adverse Events (Toxicities) |
| Time Frame: | Performed at 2.5 years after the last patient enrolled; up to 4 years. |
| Safety Issue: | |
| Description: | The rate of grade 3, 4, or 5 treatment-related non-hematologic adverse events (toxicities) by arm; excludes adverse events occurring post-crossover for patients in Arm A |
Details
| Phase: | Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Active, not recruiting |
| Lead Sponsor: | National Cancer Institute (NCI) |
Last Updated
August 27, 2021
